Expression of lysophosphatidic acid receptor 5 is necessary for the regulation of intestinal Na⁺/H⁺ exchanger 3 by lysophosphatidic acid in vivo.

Lysophosphatidic acid (LPA) is a bioactive lipid molecule, which regulates a broad range of pathophysiological processes. Recent studies have demonstrated that LPA modulates electrolyte flux in the intestine, and its potential as an antidiarrheal agent has been suggested. Of six LPA receptors, LPA₅ is highly expressed in the intestine. Recent studies by our group have demonstrated activation of Na⁺/H⁺ exchanger 3 (NHE3) by LPA₅. However, much of what has been elucidated was achieved using colonic cell lines that were transfected to express LPA₅. In the current study, we engineered a mouse that lacks LPA₅ in intestinal epithelial cells, Lpar5^ΔIEC, and investigated the role of LPA₅ in NHE3 regulation and fluid absorption in vivo. The intestine of Lpar5^ΔIEC mice appeared morphologically normal, and the stool frequency and fecal water content were unchanged compared with wild-type mice. Basal rates of NHE3 activity and fluid absorption and total NHE3 expression were not changed in Lpar5^ΔIEC mice. However, LPA did not activate NHE3 activity or fluid absorption in Lpar5^ΔIEC mice, providing direct evidence for the regulatory role of LPA₅. NHE3 activation involves trafficking of NHE3 from the terminal web to microvilli, and this mobilization of NHE3 by LPA was abolished in Lpar5^ΔIEC mice. Dysregulation of NHE3 was specific to LPA, and insulin and cholera toxin were able to stimulate and inhibit NHE3, respectively, in both wild-type and Lpar5^ΔIEC mice. The current study for the first time demonstrates the necessity of LPA₅ in LPA-mediated stimulation of NHE3 in vivo. NEW & NOTEWORTHY This study is the first to assess the role of LPA₅ in NHE3 regulation and fluid absorption in vivo using a mouse that lacks LPA₅ in intestinal epithelial cells, Lpar5^ΔIEC. Basal rates of NHE3 activity and fluid absorption, and total NHE3 expression were not changed in Lpar5^ΔIEC mice. However, LPA did not activate NHE3 activity or fluid absorption in Lpar5^ΔIEC mice, providing direct evidence for the regulatory role of LPA₅.

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